The development of short interfering RNA sequences (siRNAs) as therapeutics has been hindered by problems in delivering the siRNA to its target. siRNA rapidly undergoes enzymatic degradation resulting in a short half-life in the blood, and has poor cellular update and tissue bioavailability. As a result, there has been significant research on delivering siRNA in lipid nanoparticles (LNPs).
Many LNPs include components to minimize aggregation. The inclusion of pegylated lipids into LNPs is known to inhibit aggregation, however, PEG can affect the intracellular delivery and trafficking of non-viral vectors. See, e.g., Heyes et al., J. Control. Release, 112 (2006) 280-290. The instructions for some pharmaceuticals indicate that the formulation should be shaken before use in order to break up aggregates and minimize their effect during dosing. However, shaking may not sufficiently break-up aggregates, and there is a risk that the medical practitioner will not perform this function.
There is, therefore, a need for improved stable LNP formulations with minimal aggregation.